The OculoCerebroRenal syndrome of Lowe (OCRL) is a rare X-linked disorder of congenital cataracts, mental retardation, behavioral abnormalities, and renal tubulopathy. The renal signs of OCRL, particularly low molecular weight (LMW) proteinuria and aminoaciduria, overlap with those of Dent disease, a disorder that affects only the kidney. While most cases of Dent disease are caused by mutations in an endosomal chloride channel gene, CLCN5, mutations in OCRL1 account for ~20% of Dent disease patients. The disease is caused by loss-of-function mutations in the OCRL1 gene that encodes a phosphoinositide 5-phosphatase in the trans- Golgi network, endosomes, plasma membrane ruffles, and clathrin-coated pits. It has been proposed that the OCRL tubulopathy my result, in part, from defective receptor endocytosis, such as apical trafficking or recycling of megalin, a protein responsible for reabsorbing LMW proteins via clathrin mediated endocytosis. CNS abnormalities could arise by analogous defects in recycling of certain CNS receptors. Testing these hypotheses is hampered by the lack of a mouse model because Ocrl1 deficient mice are normal. We hypothesized that the lack of phenotype in Ocrl1 deficient mice is due to complete compensation by a paralogous enzyme, Inpp5b. Mice deficient in Inpp5b have only a mild phenotype but mutation of both Ocrl1 and Inpp5b causes early embryonic lethality, indicating functional overlap. INPP5B and Inpp5b have many differences in transcription and splicing which could explain why INPP5B only partially compensates for loss of human OCRL1 while mouse Inpp5b completely compensates. We therefore created three independent transgenic mouse lines deleted for both murine Ocrl1 and Inpp5b and carrying a bacterial artificial chromosome (BAC) containing INPP5B. In all three lines, Ocrl1-/y;Inpp5b-/-;INPP5B+ mice have reduced growth and excrete abnormal amounts of LMW protein in the urine. In contrast, Ocrl1-/y;Inpp5b-/-; INPP5B+/+ mice with two copies for the BAC insertion grow more normally and excrete much less LMW protein, while Ocrl1-/y;Inpp5b+/- mice are normal. We conclude that there is both a qualitative and quantitative difference in the ability of INPP5B and Inpp5b to compensate for loss of Ocrl1 in mice. In this current application, we will examine changes in kidney function with age as well as abnormalities in central nervous system by tests of motor function, anxiety, learning and memory. We will then examine primary proximal tubule cell cultures for defects in transport and uptake. Finally, we will look for defective endocytic function in cultured renal tubule cells. In the future, we plan to screen for small molecules that increase INPP5B expression and use these animal and cell culture models to test these molecules for their ability to ameliorate the renal phenotype. If we can identify a CNS phenotype, we can test for amelioration of that phenotype as well. Such a small molecule could eventually lead to a drug therapy for patients with Lowe syndrome.